© 2015 The Author. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. Background. We describe the spectrum of etiologies associated with temporal lobe (TL) encephalitis and identify clinical and radiologic features that distinguish herpes simplex encephalitis (HSE) from its mimics. Methods. We reviewed all adult cases of encephalitis with TL abnormalities on magnetic resonance imaging (MRI) from the California Encephalitis Project. We evaluated the association between specific clinical and MRI characteristics and HSE compared with other causes of TL encephalitis and used multivariate logistic modeling to identify radiologic predictors of HSE. Results. Of 251 cases of TL encephalitis, 43% had an infectious etiology compared with 16% with a noninfectious etiology. Of infectious etiologies, herpes simplex virus was the most commonly identified agent (n = 60), followed by tuberculosis (n = 8) and varicella zoster virus (n = 7). Of noninfectious etiologies, more than half (n = 21) were due to autoimmune disease. Patients with HSE were older (56.8 vs 50.2 years; P =. 012), more likely to be white (53% vs 35%; P =. 013), more likely to present acutely (88% vs 64%; P =. 001) and with a fever (80% vs 49%; P <. 001), and less likely to present with a rash (2% vs 15%; P =. 010). In a multivariate model, bilateral TL involvement (odds ratio [OR], 0.38; 95% confidence interval [CI],. 18-.79; P =. 010) and lesions outside the TL, insula, or cingulate (OR, 0.37; 95% CI,. 18-.74; P =. 005) were associated with lower odds of HSE. Conclusions. In addition to HSE, other infectious and noninfectious etiologies should be considered in the differential diagnosis for TL encephalitis, depending on the presentation. Specific clinical and imaging features may aid in distinguishing HSE from non-HSE causes of TL encephalitis.